This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders, such as inflammation and inflammation-related disorders.
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named xe2x80x9ccyclooxygenase-2 (COX-2)xe2x80x9d or xe2x80x9cprostaglandin G/H synthase IIxe2x80x9d) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
Recently, there has been significant research into some of the roles of cyclooxygenase-2. It has been found that COX-2 is upregulated in benign and malignant tumors (K. Subbaramaiah et al., Proc. Soc. Exp. Biol. Med., 216, 201 (1997)) including lung cancer (T. Hida et al., Anticancer Res., 18, 775-82 (1998)), Barrett""s esophagus (K. Wilson, Cancer Res., 58, 2929-34 (1998)) and skin cancer (S. Buckman et al., Carcinogenesis, 19, 723-29 (1998)). It is expressed in airway cells with implication in asthma (P. Barnes et al., Lung Biol. Health Dis., 114, 111-27 (1998)). Cox-2 also has a role in pre-term labor, angiogenesis (M. Tsujii et al. Cell, 93, 705-16 (1998)), vascular rejection (M. Bustos, J. Clin. Invest., 100, 1150-58 (1997)), HIV induced apoptosis (G. Bagetta et al., Biochem. Biophys. Res. Commun., 244, 819-24 (1998)), neurodegeneration (T. Sandhya et al., Brain Res., 788, 223-31 (1998)), inflammatory bowel disease, colitis, (I. Singer et al., Gastroenterology, 115, 297-306 (1998)), cerebral ischemia (S. Nogawa et al., Proc. Natl. Acad. Sci., 95, 10966-71 (1998)), hypertension (A. Nasjletti, Hypertension, 31, 194-200 (1997)), among others.
Drugs that inhibit cyclooxygenase affect colon cancer (T. Kawamori et al., Cancer Res., 58, 409-12 (1998)), allergic neuritis (K. Miyamoto et al., Neuro Report, 9, 2331-4 (1998)), dementia, burn infections (M. Shoup, J. Trauma: Inj., Infec., Crit care, 45, 215-21 (1998)), cytomegalovirus infectivity (E. Speir et al., Circ. Res., 83, 210-16 (1998)), lumbago (H. Bosch, Curr. Med. Res. Opin., 14, 29-38 (1997)), among others.
Japanese Patent No. 6166813 describes dihydrobenzopyrans as plastic additives. Japanese Patent No. 5032591 describes bicyclic compounds for preparing coloring materials. EP publication 736529, published Oct. 9, 1996, describes 2,2-dimethyldihydrobenzopyrans as reagents for immunoassay. U.S. Pat. No. 5,773,203, issued Jun. 30, 1998, describes tetrahydroquinoline compounds for color imagining agents. Japanese patent 10069044 describes tetrahydroquinolines as color agents. Japanese patent 10062926 describes tetrahydroquinolines as color agents. Japanese patent 10062929 describes tetrahydroquinolines as color agents. U.S. Pat. No. 5,120,862, issued Jun. 9, 1992, describes tetrahydronaphthalene carboxylic acids as intermediates. Japanese publication 4009959 describes the use of dihydrothiobenzopyrans as photographic agents. WO98/29386, published Jul. 9, 1998, describes sulfonyl substituted dihydrobenzopyran derivatives as linkers. EP670312, published Sep. 6, 1995, describes tetrahydroquinolines as color developing agents. WO98/12192 describes tetrahydroquinolines as herbicides. WO98/12180 describes tetrahydroquinolines as herbicides.
U.S. Pat. No. 4,954,518, issued Sep. 4, 1990, describes benzopyran-ones for the treatment of inflammation. EP publication 695547, published Feb., 7, 1996, describes benzopyran-ones as immunomodulators. Japanese patent 6128155 describes antiinflammatory benzopyranones. Japanese patent 5178745 describes antiinflammatory benzopyranones. Japanese publication 6227971 describes amidine derivatives as antiviral agents. Japanese publication 8020532 describes amidine derivatives as pancreatitis agents. U.S. Pat. No. 5,639,911 describes amidino compounds for the treatment of cancer. U.S. Pat. No. 5,620,991 describes amidino compounds as factor Xa inhibitors. U.S. Pat. No. 5,462,965, issued Oct. 31, 1995, describes amino alcohols for treatment of CNS disease. EP 363883 describes chroman derivatives for the treatment of carrdiovascular disease. U.S. Pat. No. 4,777,257 describes tetrahydronaphthyl acid derivatives for the inhibition of thromboxane.
U.S. Pat. No. 5,731,324, issued Mar. 24, 1998, describes benzopyran derivatives as platelet aggregation inhibitors. U.S. Pat. No. 5,618,843 describes tetrahydronaphthalene derivatives as anti-platelet agents. PCT publication WO98/08836, published Mar. 5, 1998, describes chromene-3-carboxylic acid analogs as endothelin antagonists. PCT publication WO95/04530, published Feb. 16, 1995, describes tetrahydronaphthalene analogs as endothelin antagonists. PCT publication WO98/38992, published Sep. 11, 1998, describes benzopyran analogs as remedies for peripheral circulation disturbances. U.S. Pat. No. 5,112,972, issued May 12, 1992, describes chroman derivatives for the treatment of cardiovascular disease. U.S. Pat. No. 5,387,587, issued Feb. 7, 1995, describes chroman derivatives for the treatment of cardiovascular disease. PCT publication WO96/15099, published May 23, 1996, describes tetrahydronaphthalene carboxylic acid analogs as glutamate receptor agonist/antagonists. U.S. Pat. No. 5,124,325, issued Jun. 23, 1992, describes tetrahydroquinoline-8-carboxylic acid derivatives as agents to treat metabolic bone disease. Japanese publication 9255660 describes the use of tetrahydoquinolines for the treatment of vessel wall hypertrophy inhibitors. WO93/14066 describes sulfonamide amino acid derivatives as CCK antagonists.
U.S. Pat. No. 4,889,871, issued Dec. 26, 1989, describes dihydrobenzopyran derivatives as leukotriene inhibitors. U.S. Pat. No. 5,281,600, issued Jan. 25, 1994, describes tetrahydroquinoline-8-carboxylic acid derivatives as antirheumatoid agents. WO93/15067 describes 4-hydroxy-dihydrobenzopyrans as LTB4 antagonists. U.S. Pat. No. 5,242,912, issued Sep. 7, 1993, describes tetrahydroquinoline carboxylic acid derivatives as antirheumatoid agents. WO88/03805, published Jun. 2, 1988, describes tetrahydronaphthalenes for the treatment of cancer. U.S. Pat. No. 5,698,550 describes chroman derivatives as 5-lipoxygenase inhibitors. U.S. Pat. No. 5,552,441 describes leukotriene B4 antagonists.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel dihydrobenzopyran, tetrahydroquinoline, dihydrobenzothiopyran and tetrahydronapthalene derivatives disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts.
However, compounds of the current invention have not been described as antiinflammatory cyclooxygenase-2 inhibitors.